The invention relates to fatty acid treatment.
Chemotherapy, the use of drugs which aim either to kill cancer cells or to stop the spread of cancer, is now one of the most widely used types of treatment for cancer. It may be used either alone or in combination with one of the other modalities of cancer treatment, usually surgery or radiotherapy. Most chemotherapy regimes, other than those primarily targeted at the endocrine system such as anti-oestrogens and antiandrogens, cause important side effects. These side effects differ from drug to drug, but it is now common to use two, three, four or more drugs in combination in chemotherapy regimes and so most chemotherapy-treated patients will experience one or more of the typical consequences. The side effects include nausea, vomiting, suppression of the immune system, suppression of white blood cells and platelets, hair loss, cardiovascular damage, lung damage, renal damage, nerve damage and marked fatigue and malaise. Each drug has a specific range of side effects, some of which may be particularly important and limit the dose of the drug which can be given and so reduce the likelihood of a cure. Doxorubicin and related compounds, for example, can be severely cardiotoxic and this is a common dose-limiting side effect. Bleomycin, and to a lesser extent cyclophosphamide, can be toxic to the lungs causing fibrosis. The platinum derivatives and related compounds may be very toxic to the nerves.
We have been developing gamma-linolenic acid (GLA) and related compounds, including linoleic acid (LA), dihomogammalinolenic acid (DGLA), arachidonic acid (AA), stearidonic acid (SA), alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) for the treatment of cancer. These compounds which are all polyunsaturated lipids are cytotoxic to many cancer cells at concentrations which do not harm normal cells and also have a range of anti-metastatic effects which may be operative at lower concentrations. We have come to the conclusion that many unsaturated fatty acids with carbon chain lengths from 14 to 26 and which contain two to six unsaturated double carbon-carbon bonds which may be either in the cis or the trans configuration can have anti-cancer actions. Other examples of such fatty acids include conjugated linoleic acid and parinaric acid, but the natural n-6 and n-3 EFAS are set out in the following:
The acids, which in nature are of the allxe2x80x94cis configuration, are systematically named as derivatives of the corresponding octadecanoic, eicosanoic or docosanoic acids,e.g. LA z,z-octadecaxe2x80x949,12 xe2x80x94dienoic acid or DHA z,z,z,z,z,zxe2x80x94docosaxe2x80x944,7,10,13,16,19 xe2x80x94hexanoic acid, but numerical designations based on the number of carbon atoms, the number of centres of unsaturation and the number of carbon atoms from the end of the chain to where the unsaturation begins, such as correspondingly, 18:2 n-6 or 22:6 n-3, are convenient. Initials, e.g. EPA, and shortened forms of the name e.g. eicosapentaenoic acid, are used as trivial names in some instances.
In a range of studies we have administered GLA, LA, EPA and DHA to patients with cancer and we are actively developing specific derivatives of these fatty acids as anti-cancer drugs. In many instances, the fatty acids have been given to patients who at that same time were receiving conventional chemotherapy for their cancer. We have repeatedly observed that many of the toxic side effects of chemotherapy are substantially reduced in patients who at the same time are receiving one or more of LA, GLA, EPA and DHA. On theoretical grounds, because of their similar chemical characteristics and modes of action we believe that many of the other fatty acids whose general characteristics are summarised in the previous paragraph will also have similar effects. The effects observed include reduced hair loss, reduced suppression of leukocytes and lymphocytes, reduced nausea and vomiting and in particular reduced fatigue and malaise. Our observations therefore indicate that GLA and EPA and related compounds may surprisingly have a broad spectrum of actions in reducing many different side effects of chemotherapy. We therefore propose their use in patients who are receiving chemotherapy for cancer to reduce the side effects of such chemotherapy, as set out in the claims herein.
We have recently supported the clinical observations by animal studies on the cardiotoxicity of doxorubicin and the lung toxicity of bleomycin. When 20 mg of doxorubicin (DOX) is given intraperitoneally to mice, the animals usually die within two weeks because of cardiac damage. When animals were pre-treated with LA or with GLA or with EPA or with DHA in various doses and chemical forms, the death rate to the same dose of doxorubicin was reduced to between 20% and 60% depending on the dose and the precise chemical administered. In addition the reduction in cardiac weight, which is characteristic of doxorubicin toxicity, was considerably attenuated. Similarly, bleomycin introduced into the trachea of animals under anaesthesia at a dose of about 5-10 IU per kg body weight, within 2-4 weeks the animals develop severe lung fibrosis which is very similar to the fibrosis which occurs in human patients treated with bleomycin. Treatment with gamma-linolenic acid and linoleic acid could almost entirely suppress the lung pathological changes and the increased production of fibrous tissue. In a third animal study, the anti-cancer streptozotocin was used. A major effect of this compound is to damage the islet cells of the pancreas and consequently to lead to insulin dependent diabetes. Administration of LA, GLA or EPA prior to the streptozotocin greatly reduced the likelihood of the development of diabetes in rats. The ability of the fatty acids to suppress these very different forms of toxicity and the clinical observations which have been made in patients being treated with a wide range of drugs suggest that this is a method of preventing drug toxicity which has wide applicability.
The invention is as set out in the claims, but broadly lies in the use, in preparation of a medicament for treating and preventing the side effects of anti-cancer chemotherapy, particularly the side effects caused by any of the drugs listed herein, of a polyunsaturated fatty acid with a carbon chain length of 14 to 26 and with 2 to 6 double bonds in the molecule in cis or trans configuration, and a method of such treatment or prevention wherein said fatty acid is administered.
Preferred fatty acids are LA, GLA, DGLA, SA, ALA, EPA and DHA, optionally administered or used with other fatty acids.
The drugs which have been used in anti-cancer chemotherapy in patients as referred to above include methotrexate, 5-fluorouracil, cyclophosphamide, cisplatin, doxorubicin, taxol and vincristine, but the invention provides a method of reducing the side effects resulting from any form of cancer chemotherapy resulting from drugs in any one of the classes mentioned below, or drugs similar to them which may be developed in the future:
Folate antagonists such as methotrexate and trimetrexate
Pyrimidine antagonists such as 5-fluorouracil, fluorodeoxyuridine and azacytidine.
Purine antagonists such as mercaptopurine, thioguanine, tiazofurin, chloro-deoxyadenosine and pentostatin.
Sugar modified analogues such as cytarabine and fludarabine.
Ribonucleotide reductase inhibitors such as hydroxyurea.
Nitrogen mustards such as mechlorethamine, chlorambucil, melphalan cyclophosphamide and ifosfamide.
Aziridines such as thiotepa, altretamine and mitomycin.
Alkane sulfonates such as busulfan.
Nitrosoureas such as carmustine, lomustine, semustine and streptozotocin.
Platinum compounds such as cisplatin and carboplatin.
Methylating agents such as dacarbazine and procarbazine.
DNA-binding drugs such as daunorubicin, doxorubicin, idarubicin, epirubicin, mitoxantrone, dactinomycin, bleomycin and plicamycin.
Topoisomerase inhibitors such as etoposide, teniposide, amascrine, camptothecin.
Microtubule active agents such as vinblastine, vincristine, vindosine, taxol and taxotere.
The fatty acids may be administered at the same time as the anti-cancer drugs or preferably both prior to and during therapy with the anti-cancer drugs themselves administered in amounts appropriate for the individual drug. The doses of the fatty acids may be from 1 mg to 100 g per day, preferably 50 mg to 50 g per day and very preferably 500 mg to 20 g per day. The fatty acids may be given in any appropriate form which leads to an elevation of the fatty acid in the blood and cell membranes, including free fatty acids, simple esters of various sorts, salts including lithium salts, mono-, di- and tri-glycerides, mono- and di-esters of dihydric alcohols, ascorbyl and niacin derivatives, cholesterol esters, phospholipids and any other appropriate carriers. They may be given orally, parenterally or topically using any appropriate carrier or delivery systems or excipients known to those skilled in the art, including capsules, tablets, powders, liquids, emulsions and any other appropriate method.